Cell Cycle Dependent Regulation of Human Progesterone in Breast Cancer
Abstract
Breast cancers are often characterized by increased growth factor signaling pathways and numerous cell cycle alterations. PR are phosphorylated by CDK2 in vitro and in vivo at multiple sites including serine 400 (Ser400). The purpose of these studies is to investigate the role that growth factors and cell cycle molecules play on the regulation of PR by phosphorylation of Ser400. Treatment of T47D breast cancer cells with mitogens increased the phosphorylation of PR Ser400, as did the synthetic progestin R5020. Progestin dependent phosphorylation of Ser400 was reversed by a CDK2 inhibitor. Overexpression of cyclin E and CDK2 resulted in downregulation of PR protein in the absence of ligand. This effect was blocked by a CDK2 inhibitor. P27 is a cyclin-dependent kinase inhibitory protein. A p27-/-cell line was used to measure the transcriptional activity of PR following transient co-transfection of PR and a progesterone responsive-element Ligand-independent PR transcriptional activity was elevated in p27-/-cells; mutation of PR serine 400 to alanine resulted in loss of PR transcriptional activity. In' addition, cyclin E and CDK2 associated with wt PR in co-immunoprecipitation experiments. Regulation of PR by altered cyclin/CDKs may confer a selective advantage to breast cancer cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2003
- Accession Number
- ADA418821
Entities
People
- Lisa K. Mullany
Organizations
- University of Minnesota